1-(adamantyl)amidines and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission

ABSTRACT

Compounds of 1-(adamantyl) amidine and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmittion.

This application is a 371 of PCT/GB98/03715 filed Dec. 11, 1998, now WO99/31051.

The present invention relates to compounds and compositions for use inthe treatment of conditions generally associated with abnormalities inglutamatergic transmission.

The excitatory neurotransmission underlying brain function is primarily(about 80 per cent) dependent on the action of glutamate and otherrelated neurotransmitters on specific receptors activated by theexcitatory amino acids. These receptors fall into several categories,one of which is the glutamate receptor specifically sensitive to theagonist N-methyl-D-aspartate (the NMDA receptor). NMDA receptor subtypesare ubiquitously expressed in mamnmalian brain and have uniqueproperties underlying their role in synaptic function and plasticity. Inview of the central role of these receptors in normal central nervoussystem function, numerous suggestions have been made as to the utilityof drugs acting at this receptor to modulate the processes underlyingvarious disease states. The NMDA receptor has been studied withparticular interest in relation to its apparent involvement in thepathophysiology of neurodegenerative diseases.

Non-competitive antagonists at this receptor should be particularlyadvantageous in the treatment of diseases since such compounds wouldhave activity that should not be overcome by high levels of endogenousagonists and would act equally well independent of the endogenousagonist activating the receptor. This is important since high levels ofendogenous glutamate can occur in certain pathological processes andthere are a variety of different endogenous agonists that can actthrough a variety of specific modulatory agonist binding sites on thereceptor.

A number of NMDA antagonists have been disclosed which operate bybinding to the ion-channel of the NMDA receptor. The advantage ofchannel blockers is that they operate only on the “open” channel andtherefore do not affect unactivated receptors. In addition they areeffective regardless of the mechanism of receptor stimulation and theireffect will not be diminished by large concentrations of endogenousagonist.

Given that the NMDA receptor plays a primary role in normal centralnervous system function, it is not surprising that certain drugs actingto block or antagonise the function of this receptor affect normalfunction within the brain. This may be manifested as central nervoussystem side effects such as hallucinations, confusion, paranoia,aggression, agitation and catatonia. These side effects can be describedas a psychotic state and the drugs that induce them are known aspsychotomimetic NMDA antagonists. Such side effects limit the utility ofthese compounds in treating disease states. NMA receptor antagoniststhat have efficacy in treating central nervous system disorders butwithout such psychotomimetic side effects would have a clear therapeuticadvantage. Thus, in view of the crucial role played by the NMDA receptorin either the progression or expression of the disease pathology andprocess, it is an object of this invention to provide compounds for thetreatment of central nervous system disorders which modulate theactivity of the NMDA receptor but which are well-tolerated in the senseof having a markedly reduced propensity to induce psychotomimetic sideeffects.

The present invention is particularly concerned with the treatment ofneurodegenerative disorders. There is a large body of evidence tosuggest that either an excitotoxic or slow excitotoxic pathologicalover-activation of the NMDA receptor induces the death of neurons in avariety of disorders such as ischaemic stroke, other forms of hypoxicinjury, haemorrhagic brain injury, traumatic brain injury, Alzheimer'sdisease, Parkinson's disease, Huntington's disease and other dementingdiseases. There is thus clear evidence that antagonism of the NMDAreceptor will reduce or prevent the neurodegeneration that underlies thedisease process in these and related conditions. There is also evidenceto suggest that a well tolerated compound will allow effectivesymptomatic treatment of the manifestations of the disease process inthese disorders as well as reducing the primary underlyingneurodegeneration process. Also, it is known that disorders previouslydescribed as involving acute neurodegeneration have longer than expectedelevations in glutamate release and consequently require longer thanexpected treatment with NMDA antagonists. There would therefore be atherapeutic advantage for new drugs which are well tolerated and whichcan therefore be administered chronically.

The published literature contains references to a number of compoundsand classes of compounds purported to be useful as NMDA antagonists.

The compounds Amantadine and Memantine and related anti-viral agentshave been known for many years.

Patent applications have been filed directed to the use of Memantine inthe treatment of Parkiinson's Disease in the 1970s and as an NMDAantagonist in 1990 (see EP-A-0392059 and U.S. Pat. No. 5,061,703).Furthermore, International Patent application WO94/05275 proposes theuse of Amantadine and related compounds such as Memantine in thetreatment and prevention of non-ischaemic, long term NMDAreceptor-mediated neuronal degeneration. An increase in affinity for theNMDA receptor due to substitution of the adamantane ring of Memantinewith alkyl groups was noted and published by Komthuber et al., Eur. J.Pharmacol., 1991, 206, 297-300, by Kroemer et al., J. Med. Chem., 1998,41, 393-400 and by Parsons et al., Neuropharmacology, 1995, 34,1239-1258.

1-(Adamantyl)amidines are disclosed as antivirals in DE-A-2306784,JP-A-7391049, DD-A-151447 and GB-1478477. 1-(Adamantyl)acetamidine isdisclosed in JP-A-120683 and GB-1478477. 1-(Adamantyl)amidrazones aredisclosed as insecticides and acaricides in EP-A-0604798.N-substituted-1-(adamantyl)amidines are disclosed by May et al.,Arzneim. Forsch., 1978, 28, 732-735, and the virostatic activities ofthe compounds reported. N-substituted-1-(adamantyl)amidines asantivirals are disclosed by Skwarski et al., Acta. Pol. Pharm., 1988,45, 395-399.

The antiviral activities of adainantane derivatives including1-(adamantyl)carbamidine and 1-(adamantyl)acetamidine are reported byInamoto et al., J. Med. Chem., 1975, 18, 713-721, where they arecompared with Amantadine.

As discussed above, psychotomimetic side-effects are observed during theuse of a number of well known NMDA channel blockers and therefore itwill be a considerable advantage to identify clinically well-toleratedantagonists where such side effects are minimised. Porter and Greenamyre(J. Neurochem. 1995, 64, 614-623; incorporated herein by reference)demonstrated that well tolerated and psychotomimnetic NMDA receptorchannel blockers could be differentiated on the basis of their relativeaffinities for forebrain and cerebellar receptors irrespective ofabsolute affinities. Selectivity for cerebellar NMDA receptors overforebrain NMDA receptors is observed for well-tolerated compounds. Thebasis of this observation may be related to different populations ofNMDA receptor subtypes in these brain regions.

The use of a number of the known NOMA antagonists such as Dizocilpine,PCP, Cerestat and Ketamine gives rise to a number of side effects whichrender these compounds unsuitable for use in treatment. In particular,administration of the compounds is associated with perceptual andcognitive disturbances of a kind that resemble naturally-occurringpsychotic states.

In addition, the perceptual and cognitive side effects of the compoundsbecome more pronounced after the onset of puberty and sexual maturation,and these compounds are therefore particularly unsuitable for thetreatment of adults. This developmental change has been demonstratedempirically in both experimental animals and in man, and is paralleledin experimental animals by brain hypermetabolism.

In summary, there is a need for an NMDA antagonist which is welltolerated and does not give rise to the side effects associated withprevious clinically investigated NMDA antagonists.

A number of compounds have now been found that show affinity for theNMDA receptor and are useful in the treatment of conditions generallyassociated with abnormalities in glutamatergic transmission such asstroke, traumatic brain injury and neurodegenerative diseases such asParkinson's and Alzheimer's diseases. It has also been found that thecompounds have a surprisingly favourable ratio of cortex to cerebellarbinding affinity which indicates that these compounds should be welltolerated in vivo.

According to the present invention there is provided use of a compoundof the formula (1):

wherein

X is an allylene chain comprising 0, 1, 2, 3 or 4 carbon atoms;

R¹, R² and R³ are independently selected from hydrogen, alkyl and aryl;

R⁴, R⁵ and R⁶ are independently selected from hydrogen, alkyl, aryl,halogen and alkoxy;

and prodrugs thereof and pharmaceutically acceptable salts thereof;

in the manufacture of a medicament for use in the treatment of acondition generally associated with abnormalities in glutamatergictransmission.

As used herein, the term “alkyl” means a branched or unbranched, cyclicor acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl)hydrocarbyl radical. Where cyclic, the alkyl group is preferably C₃ toC₁₂, more preferably C₅ to C₁₀, more preferably C₅ to C₇. Where acyclic,the alkyl group is preferably C₁ to C₁₀, more preferably C₁ to C₆, morepreferably methyl, ethyl or propyl, more preferably methyl or ethyl.

As used herein, the term “aryl” means an aromatic group, such as phenylor naphthyl, or a heteroaromatic group containing one or more,preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl andthiophenyl. Preferably, the aryl group comprises phenyl.

The alkyl and aryl groups may be substituted or unsubstituted,preferably unsubstituted. Where substituted, there will generally be 1to 3 substituents present, preferably 1 substituent. Substituents mayinclude:-

carbon containing groups such as

alkyl,

aryl, arylalkyl; (e.g. substituted and unsubstituted phenyl, substitutedand unsubstituted benzyl)

halogen atoms and halogen containing groups such as

haloalkyl (e.g. trifluoromethyl);

oxygen containing groups such as

alcohols (e.g. hydroxy, hydroxyalkyl, (aryl)(hydroxy)alkyl),

ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g.carboxaldehyde),

ketones(e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,arylalkylcarbonyl, arylcarbonylalkyl) acids (e.g. carboxy,carboxyalkyl),

acid derivatives such as esters (e.g. alkoxycarbonyl,alkoxycarbonylalkyl, alkycarbonylyoxy, alkycarbonylyoxyalkyl)

and amides (e.g. aminocarbonyl, mono- or dialkylaminocarbonyl,aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl,arylaminocarbonyl);

nitrogen containing groups such as

amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl),

azides,

nitriles (e.g. cyano, cyanoalkyl),

nitro;

sulphur containing groups such as

thiols, thioethers, suphoxides, and sulphones (e.g. alkylthio,alkylsulfinyl, alkylsufonyl, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,arylsulfinylalkyl, arylsulfonylalkyl)

and heterocyclic groups containing one or more, preferably one,heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl,pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl,morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl,oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl,isoindazolyl, benzopyranyl, coumarinyl, isocounarinyl, quinolyl,isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl,benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl andcarbolinyl).

As used herein, the term “alkoxy” means alkyl-O— and “alkoyl” meansalkyl-CO—.

As used herein, the term “halogen” means a fluorine, chlorine, bromineor iodine radical, preferably a bromine or chlorine radical.

As used herein the term “conditions generally associated withabnormalities in glutamatergic transmission” primarily includesischaemic stroke, haemorrhagic stroke, subarrachnoid haemorrhage,subdural haematoma, coronary artery bypass surgery, neurosurgery,traumatic brain injury, traumatic spinal injury, Alzheimer's disease,Parkinson's disease, Huntington's disease, Pick's disease, Lewy bodydisease, senile dementia, spongiform encephalopathies, prion-proteininduced neurotoxicity, peri-natal asphyxia, demyelinating disease,multiinfarct dementia, dementia pugilans, drug dependence, alcoholwithdrawal, opiate withdrawal, motor neurone disease, multiplesclerosis, acute and chronic pain including neuropathic pain, cancerpain, trigeminal neuralgia, migraine, primary and secondaryhyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis,phantom limb pain, spinal cord injury pain, central pain, post-herpeticpain, HIV pain and diabetic neuropathy. In addition, the term alsoincludes the following conditions: epilepsy, multiple system atrophy,progressive supra-nuclear palsy, Friedrich's ataxia, autism, fragile Xsyndrome, tuberous sclerosis, attention deficit disorder,olivio-ponto-cerebellar atrophy, cerebral palsy, drug-induced opticneuritis, peripheral neuropathy, myelopathy, ischaemic retinopathy,glaucoma, cardiac arrest, encephalitis, depression, bi-polar disorder,schizophrenia, psychosis, behaviour disorders, impulse controldisorders, pre-eclampsia, neuroleptic malignant syndrome, chronicfatigue syndrome, anorexia nervosa, anxiety disorders, generalisedanxiety disorder, panic disorder, phobias, fresh water drowning anddecompression.

As used herein, the term “pharmaceutically acceptable salt” means anypharmaceutically acceptable salt of the compound of formula (1). Saltsmay be prepared from pharmaceutically acceptable non-toxic acidsincluding inorganic and organic acids. Such acids include acetic,benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic,ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.Particularly preferred are hydrochloric, hydrobromic, phosphoric, andsulfuric acids, and most particularly preferred is the hydrochloridesalt.

The compounds of formula (1) may exist in a number of diastereomericand/or enantiomeric forms. Reference in the present specification to “acompound of formula (1)” is a reference to all stereoisomeric forms ofthe compound and includes a reference to the unseparated stereoisomersin a mixture, racemic or non-racemic, and to each stereoisomer in itspure form.

The compounds of the present invention are active as NMDA antagonistsand are well tolerated in that side effects are minimised. Experimentaldata are shown in Table 1.

In the compound of formula (1), preferably X is an alkylene chaincomprising 0, 1 or 2 carbon atoms, more preferably 0 carbon atoms, inthe chain.

In one embodiment of the invention, in the compound of formula (1),where X is an alkylene chain comprising 1, 2, 3 or 4 carbon atoms, oneor more of the carbon atom(s) in the chain X may be independentlysubstituted by substituent group(s) selected from alkyl and aryl. Wheresubstituted, a carbon atom may have one or two substituents, preferablyone. Preferred substituent groups are selected from methyl, ethyl,phenyl and benzyl, preferably ethyl and benzyl. Where X is substituted,it is preferred that only one carbon atom in the chain is substituted.

In an alternative embodiment of the invention, in the compound offormula (1), X is unsubstituted and has the formula (CH₂)_(n) where n=0to 4, preferably n=0, 1 or 2 and more preferably n=0.

In the compound of formula (1), preferably R¹ and R² are hydrogen and R³is selected from hydrogen, alkyl and aryl. In a preferred embodiment,R¹, R² and R³ are hydrogen.

In the compound of formula (1), preferably at least one of R⁴, R⁵ and R⁶is alkyl, aryl, halogen or alkoxy. Preferably R⁴ is selected fromhydrogen, alkyl and halogen, more preferably alkyl and more preferablymethyl. Preferably R⁵ is selected from hydrogen and alkyl, preferablyhydrogen and methyl. Preferably R⁶ is selected from hydrogen and alkyl,preferably hydrogen and methyl.

In a preferred embodiment, the compound of formula (1) is a compoundwhere X has 1 carbon atom (i.e. n=1) and is unsubstituted; R¹, R² and R³are hydrogen; R⁴ and R⁵ are methyl; and R⁶ is hydrogen.

In a further preferred embodiment, the compound of formula (1) is acompound where X has one carbon atom (i.e. n=1) and is substituted by anethyl or benzyl group; and R¹, R², R³, R⁴, R⁵ and R⁶ are hydrogen.

In a particularly preferred embodiment, the compound of formula (1) is acompound of formula (1) where X has 0 carbon atoms (i.e. n=0); R¹, R²and R³ are hydrogen; R⁴ and R⁵ are CH₃; and R⁶ is hydrogen.

In a further particularly preferred embodiment, the compound of formula(1) is a compound where X has 0 carbon atoms (i.e., n=0); R¹, R² and R³are hydrogen; R⁴ is methyl; and R⁵=R⁶=hydrogen or methyl.

The present invention further provides a method of treatment ofconditions generally associated with abnormalities in glutamatergictransmission comprising administering to a patient an effective dose ofa compound of formula (1) as defined above.

The present invention also provides a compound per se of the formula (1)as defined above wherein at least one of R⁴, R⁵ and R⁶ is alkyl, aryl,halogen or alkoxy, with the proviso that if R¹, R² and R³ are hydrogenand R⁴, R⁵ and R⁶ are independently selected from hydrogen and C₁₋₄alkyl, then either X is an alkylene chain of 2-4 carbon atoms,substituted or unsubstituted, as defined above, or X is an alkylenechain of 1 carbon atom substituted with one or two, preferably one,substituent group(s) independently selected from alkyl and aryl, andprodrugs and pharmaceutically acceptable salts thereof.

The present invention also provides a compound per se of the formula (1)as defined above wherein R⁴, R⁵ and R⁶ are hydrogen and either X is analkylene chain of 2-4 carbon atoms, substituted or unsubstituted, asdefined above, or X is an alkylene chain of 1 carbon atom substitutedwith one or two, preferably one, substituent group(s) independentlyselected from alkyl and aryl, or X is a CH₂ group, with the proviso thatwhere X is a CH₂ group then at least one of R¹, R² and R³ are selectedfrom alkyl and aryl, and prodrugs and pharmaceutically acceptable saltsthereof.

The present invention also provides compounds per se of formulae (2),(3), (4) and (5):

and prodrugs and pharmaceutically acceptable salts thereof.

The present invention also provides, for use in therapy:

(i) a compound of the formula (1) as defined above wherein at least oneof R⁴, R⁵ and R⁶ is alkyl, aryl, halogen or alkoxy, with the provisothat if R¹, R² and R³ are hydrogen and R⁴, R⁵ and R⁶ are independentlyselected from hydrogen and C₁₋₄ alkyl, then either X is an alkylenechain of 2-4 carbon atoms, substituted or unsubstituted, as definedabove, or X is an alkylene chain of 1 carbon atom substituted with oneor two, preferably one, substituent groups independently selected fromalkyl and aryl;

(ii) a compound of the formula (1) as defined above wherein R⁴, R⁵ andR⁶ are hydrogen and either X is an alkylene chain of 2-4 carbon atoms,substituted or unsubstituted, as defined above, or X is an alkylenechain of 1 carbon atom substituted with one or two, preferably one,substituent groups independently selected from alkyl and aryl, or X is aCH₂ group, with the proviso that where X is a CH₂ group then at leastone of R¹, R² and R³ are selected from alkyl and aryl; and

(iii) a compound of formula (2), (3), (4) or (5) as defined above,

and prodrugs and pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical compositioncomprising:

(i) a compound of the formula (1) as defined above wherein at least oneof R⁴, R⁵ and R⁶ is alkyl, aryl, halogen or alkoxy, with the provisothat if R¹, R² and R³ are hydrogen and R⁴, R⁵ and R⁶ are independentlyselected from hydrogen and C₁₋₄ alkyl then either X is an alkylene chainof 2-4 carbon atoms, substituted or unsubstituted, as defined above, orX is an alkylene chain of 1 carbon atom substituted with one or two,preferably one, substituent group independently selected from alkyl andaryl; or

(ii) a compound of the formula (1) as defined above wherein R⁴, R⁵ andR⁶ are hydrogen and either X is an alkylene chain of 2-4 carbon atoms,substituted or unsubstituted, as defined above, or X is an alkylenechain of 1 carbon atom substituted with one or two, preferably one,substituent groups independently selected from alkyl and aryl, or X is aCH₂ group, with the proviso that where X is a CH₂ group then at leastone of R¹, R² and R³ are selected from alkyl and aryl; or

(iii) a compound of formula (2), (3), (4) or (5) as defined above,

and prodrugs and pharmaceutically acceptable salts thereof, incombination with a pharmaceutically acceptable excipient.

According to a further aspect of the present invention there is provideda method of preparing the compounds of the present invention. Compoundsof formula (1) may be prepared by conventional synthetic routes; see forexample DD-A-151447, U.S. Pat. No. 5,061,703, DE-A-2306784, GB-1478477,Skwarski et al., Acta. Polon. Pharm., (1988), 45, 395-399 and May etal., Arzneim. Forsch., (1978), 28, 732-735, the disclosures of which areincorporated herein by reference.

The following reaction schemes describe examples of synthetic routes forthe preparation of compounds falling within formula (1). The reactionschemes are included for the purpose of exemplification only and are notintended to be limiting to the invention.

Compounds of formula (1) may be synthesised by conventional syntheticmethods as illustrated in Scheme 1.

Amidines of formula 4 may be synthesised from nitrites of formula 3 byconventional methods, for example by treatment with an amine in thepresence of trimethyl aluminium in a refluxing solvent such as toluenefor several days, or alternatively by treatment with HCl in dry methanolat 0° C. for several days followed by treatment with NH₃ at roomtemperature. Nitriles of formula 3 may be synthesised from carboxylicacids of formula 2 by conventional methods, for example by treatmentwith methanesulphonyl chloride in the presence of pyridine, followed bytreatment with NH₃, followed by treatment with methanesulphonyl chloridein the presence of pyridine. Carboxylic acids of formula 2 are eithercommercially available or may be synthesised by conventional methodssuch as those published in Stetter et al., Chem. Ber., 1962, 95,667-672, by Koch et al., Chem. Ber., 1963, 96, 213-219, by Stepanov etal., Zh. Obstrich. Khim., 1964, 34, 579-584, by Stepanov et al., Zh.Org. Khim., 1965, 1, 280-283 and by Stepanov et al., Zh. Org. Khim.,1966, 2, 1612-1615.

An alternative route for the preparation of compounds of formula (1)where X is CR⁷R⁸ wherein R⁷ and R₁ are independently hydrogen or alkyland wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in formula (1),also involving conventional methods, is illustrated in Scheme 2.

Amidines of formula 7 may be prepared from nitriles of formula 6 asdescribed above. Nitriles of formula 6 may be prepared from nitriles offormula 5 by alkylation or dialkylation, for example by treatment with abase such as LDA followed by treatment with an alkyl halide. Furthertreatment with a base followed by a second alkyl halide would give thedialkylated nitrile.

An alternative route for the preparation of compounds of formula (1)where X is CHR⁹CH₂ or CH₂CHR¹⁰ wherein R⁹ and R¹⁰ are independentlyalkyl or aryl and wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as definedabove, also involving conventional methods, is illustrated in Scheme 3.

Amidines of formula 11 may be prepared from nitriles of formula 10 asdescribed above. Nitriles of formula 10 may be prepared by reduction ofunsaturated nitrites of formula 9, for example by hydrogenation in thepresence of a transition metal catalyst such as palladium on carbon.Nitriles of formula 9 may be prepared from ketones or aldehydes offormula 8 by conventional methods such as the Homer-Emmons olefinationreaction using an appropriately substituted phosphonate in the presenceof a base such as sodium hydride. Ketones or aldehydes of formula 8 arecommercially available or may be synthesised by conventional methods.

In addition, compounds of formula (1) where X is an alkylene chain of 3or 4 carbon atoms may be synthesised by conventional methods asillustrated in Scheme 4. In Scheme 4, R¹, R², R³, R⁴, R⁵ and R⁶ are asdefined above and R⁹, R¹⁰, R¹¹ and R¹² are independently selected fromhydrogen, alkyl and aryl.

Anidines of formula 16 and 17 may be synthesised from nitrites offormula 15 and 12 respectively by the methods described in Scheme 1.Nitriles of formula 15 may be synthesised from nitrites of formula 14 bymethods described in Scheme 3 or alternatively from ketones of formula13 by reduction to the alcohol followed by tosylation or bromination,followed by cyanide displacement. Nitriles of formula 14 may besynthesised from ketones of formula 11 by methods described in Scheme 3.Ketones of formula 13 may be synthesised from nitrites of formula 12 bythe addition of a Grignard reagent followed by hydrolytic work-up.Nitriles of formula 12 may be prepared from ketones of formula 11 by thereduction, tosylation/bromination and cyanide displacement sequencedescribed above. Ketones of formula 11 may be prepared from nitrites offormula 10 by Grignard reactions as described above. Additionalsubstituents may be introduced into the alkylene chain X by methodsanalagous to those described in the above schemes and by otherconventional synthetic methods.

The compound of formula (1) may be administered in a form suitable fororal use, for example a tablet, pellet, capsule, aqueous or oilysolution, suspension or emulsion; for topical use including transmucosaland transdermal use, for example a cream, ointment, gel, aqueous or oilsolution or suspension, salve, patch or plaster; for nasal use, for aexample a snuff, nasal spray, nasal powder or nasal drops; for vaginalor rectal use, for example a suppository or pessary; for administrationby inhalation, for example a finely divided powder or a liquid aerosol;for sub-lingual or buccal use, for example a tablet or capsule; forocular use, for example a sterile aqueous solution or sterile ointment;or for parenteral use (including intravenous, subcutaneous,intramuscular, intravascular or infusion), for example a sterile aqueousor oil solution or suspension or emulsion, or depot injectionformulation. In general the above compositions may be prepared in aconventional manner using conventional excipients, using standardtechniques, including controlled release technologies, such as gelatin,lipid, gel depot, liposome and microcapsule based systems well known tothose skilled in the art of pharmacy.

For oral administration, the compounds of the invention will generallybe provided in the form of tablets or capsules or as an aqueous solutionor suspension.

Tablets or pellets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavouring agents, colouring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate, calcium hydrogen phosphate, cellulose derivatives andlactose, while corn starch and alginic acid are suitable disintegratingagents. Binding agents may include starch, gelatin andpolyvinyl-pyrrolidone derivatives, while the lubricating agent, ifpresent, will generally be magnesium stearate, stearic acid or talc. Ifdesired, the tablets may be formulated or coated with a material such asglyceryl monostearate or glyceryl distearate or polymethacrylatepolymers, cellulose derivatives or other pharmaceutically acceptablepolymer, to delay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredient is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,the compounds of the invention will generally be provided in sterileaqueous solutions or suspensions or emulsions, buffered to anappropriate pH and isotonicity. Suitable aqueous vehicles includeRinger's solution and isotonic sodium chloride. Aqueous suspensionsaccording to the invention may include suspending agents such ascellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gumtragacanth, and a wetting agent such as lecithin. Suitable preservativesfor aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

Transdermal formulations include membrane permeation systems,multi-laminate adhesive dispersion systems and matrix dispersionsystems. Transdermal delivery also includes the use of electricallyaided transport and skin penetration enhancers and needle-free injectiondevices.

The preferred route of administration will be as an intravenousinfusion, preferably over a period of up to seven days, or as an oralformulation, or as an intramuscular injection via a styrette or as asubcutaneous injection.

It will be appreciated that the dosage levels used may vary over quite awide range depending upon the compound used, the severity of thecondition exhibited by the patient and the patient's body weight.However, without commitment to a rigid definition of dosages it may bestated that a daily dosage of the active constituent (estimated as thefree base) is 100 μg to 800 mg. More particularly, the preferredcompounds may be administered at a preferred dose of 50-800 mg/day, insingle or divided doses.

The invention will now be described in detail. It will be appreciatedthat the invention is described by way of example only and modificationof detail may be made without departing from the scope of the invention.

EXPERIMENTAL I Synthesis Example 13,5-Dimethyl-1-adamantanecarboximidamide hydrochloride

3,5-Dimethyl-1-adamantanecarbonitrile

A solution of 3,5-dimethyl-1-adamantanecarboxylic acid (2.51 g, 12.1mmol) in dry pyridine (40 mL) at 0° C. was treated dropwise withmethanesulphonyl chloride (1.4 g, 12.2 nmmol), stirred for 2 h,saturated with ammonia gas, stirred for 5 min and the excess ammoniaremoved in vacuo. The resulting suspension at 0° C. was treated withmethanesulphonyl chloride (11.8 g, 102 mmol), stirred overnight at roomtemperature, poured into cold 1-M HCl (200 mL) and extracted with EtOAc(3×40 mL). The organic phase was washed with dilute HCl (50 mL), water(50 mL), dried (MgSO₄), concentrated in vacuo and the residue purifiedby chromatography [SiO₂; CH₂Cl₂] to give the product (1.97 g, 86%) as apale brown oil: IR ν_(max) (liquid film)/cm⁻¹ 2922, 2849, 2235, 1455,1359 and 1098; NMR δ_(H) (400 MHz, CDCl₃) 0.87 (6H, s), 1.19 (2H, s),1.3-1.45 (4H, m), 1.55-1.75 (4H, m), 1.8-1.9 (2H, m) and 2.1-2.15 (1H,m).

3,5-Dimethyl-1-adamantanecarboximidamide hydrochloride

A solution of 3,5-dimethyl-1-adamantanecarbonitrile (1.95 g, 10.3 mmol)in MeOH (30 mL) at 0° C. was saturated with HCl gas over 30 min, left at0° C. for 5 days, concentrated in vacuo, the residue triturated withEtOAc and filtered to give the intermediate imidate hydrochloride salt(1.16 g, 44%) as a hygroscopic solid. The solid (302 mg, 1.17 mmol) inMeOH (20 mL) at 0° C. was saturated with ammonia gas, left at roomtemperature for 4 days, concentrated to a small volume in vacuo, treatedwith EtOAc and filtered to give the title compound (240 mg, 85%) as awhite crystalline solid: mp 297-229° C.; IR ν_(max) (Nujol)/cm⁻¹ 3166,1673, 1508, 1087 and 729; NMR δ_(H) (400 MHz, DMSO-d₆) 0.85 (6H, s),1.20-1.50 (2H, m), 1.30-1.40 (4H, m), 1.40-1.60 (4H, m), 1.69 (2H, m),2.12 (2H, m), 8.55 (2H, br s) and 8.90 (2H, br s); Anal. Calcd forC₁₃H₂₃N₂Cl.0.1 H₂O: C, 68.84; H, 9.56; N, 11.45. Found: C, 63.73; H,9.34; N, 11.46.

Example 2 3-Chloro-1-adamantanecarboximidamide hydrochloride

3-Chloro-1-adamantanecarbonitrile

This was prepared from 3-chloro-1-adamantanecarboxylic acid by themethod of example 1 and the product isolated (2.12 g, 94%) as a palebrown solid: mp 156-157° C.; IR ν_(max) (Nujol)/cm⁻¹ 2249, 2230, 1248,1124, 972 and 734; NMR δ_(H) (400 MHz, CDCl₃) 1.64-1.73 (2H, m),1.96-2.04 (4H, m), 2.07-2.16 (4H, m), 2.25-2.30 (2H, m) and 2.38 (2H,s); Anal. Calcd for C₁₁H₁₄NCl: C, 67.52; H, 7.21; N, 7.15. Found: C,67.52; H, 7.18; N, 6.94.

3-Chloro-1-adamantanecarboximidamide hydrochloride

This was prepared from 3-chloro-1-adamantanecarbonitrile by the methodof example 1 and the title compound isolated (272 mg, 96%) as a whitecrystalline solid: mp 215-216° C.; IR ν_(max) (Nujol)/cm⁻¹ 3455, 3376,3306, 3148, 1687, 1667, 1082, 837, 733 and 701; NMR δ_(H) (400 MHz,DMSO-d₆) 1.55-1.65 (2H, m), 1.80-1.90 (4H, m), 2.05-2.15 (4H, m), 2.25(2H, s), 2.28 (2H, s), 8.70 (2H, s) and 9.04 (2H, s); Anal. Calcd forC₁₁H₁₈N₂Cl₂.H₂O.0.1 NH₄Cl: C, 48.48; H, 7.54; N, 10.79. Found: C, 48.81;H, 7.63; N, 10.86.

Example 3 3-Bromo-1-adamantanecarboximidamide hydrochloride

This was prepared from 3-bromo-1-adamantanecarbonitrile by the method ofexample 1 and the title compound isolated (276 mg, 97%) as a whitecrystalline solid: mp 221-223° C.; IR ν_(max) (Nujol)/cm⁻¹ 3453, 3373,3307, 3152, 1687, 1667, 1081, 825, 722, 699 and 679; NMR δ_(H) (400 MHz,DMSO-d₆) 1.60-1.70 (2H, m), 1.85-1.95 (4H, m), 2.21 (2H, s), 2.25-2.35(4H, m), 2.50 (2H, s) and 8.8 (4H, br s); Anal. Calcd forC₁₁H₁₈N₂BrCl.H₂O: C, 42.39; H, 6.47; N, 8.99. Found: C, 42.17; H, 6.48;N, 9.08.

Example 4 3-Ethyl-1-adamantanecarboximidamide hydrochloride

This was prepared from 3-ethyl-1-adamantanecarbonitrile by the method ofexample 1 and the title compound isolated (1.74 g, 94%) as a whitecrystalline solid: mp 210-212° C.; IR ν_(max) (Nujol)/cm⁻¹ 3266, 3070,1665, 1089 and 734; NMR δ_(H) (400 MHz, DMSO-d₆) 0.79 (3H, t, J7.75 Hz),1.1-1.2 (2H, m), 1.35-1.45 (4H, m), 1.7-1.85 (2H, m), 2.09 (2H, s), 8.56(2H, br s) and 8.92 (2H, br s); Anal. Calcd for C₁₃H₂₃N₂Cl: C, 64.31; H,9.55; N, 11.53.Found: C, 64.05; H, 9.95; N, 11.49.

Example 5 3,5-Dimethyl-1-adamantaneacetiniidamide hydrochloride

3, 5-Dimethyl-1-adamantaneacetonitrile

This was prepared from 3,5-dimethyl-1-adamantaneacetic acid (Bott andHellman, Angew. Chem. Int. Ed. Engl., 1966, 5,870, the disclosure ofwhich is incorporated herein by reference) by the method of example 1and the product isolated (833 mg, 88%) as a pale brown oil: IR ν_(max)(liquid film)/cm⁻¹ 2900, 2843, 2244, 1455, 1360 and 1345; NMR δ_(H) (400MHz, CDCl₃) 0.84 (6H, s), 1.1-1.3 (6H, m), 1.32-1.35 (2H, m), 1.44-1.47(2H, m), 2.12 (2H, s) and 2.05-2.15 (1H, m).

3,5-Dimethyl-1-adamantaneacetimidamide hydrochloride

This was prepared from 3,5-dimethyl-1-adamantaneacetonitrile by themethod of example 1 and the title compound isolated (778 mg, 100%) as awhite crystalline solid: mp 252-253° C.; IR ν_(max) (Nujol)/cm⁻¹ 3384,3076, 1691 and 722; NMR δ_(H) (400 MHz, DMSO-d₆) 0.81 (6H, s), 1.0-1.25(6H, m), 1.25-1.35 (4H, m), 1.38 (2H, s), 2.04 (1H, m), 2.17 (2H, s) and8.76 (4H, br s); Anal. Calcd for C₁₄H₂₅N₂Cl.0.9 H₂O: C, 61.59; H, 9.89;N, 10.26. Found: C, 61.69; H, 10.31; N, 10.19.

Example 6 N-Allyl-3,5-dimethyl-1-adamantanecarboximidamide hydrochloride

This was prepared from 3,5-dimethyl-1-adamantanecarbonitrile by themethod of example 1 using allylamine (3 eq) instead of ammonia. Thetitle compound was isolated (46 mg, 42%) as a white crystalline solid:mp 222-224° C.; IR ν_(max) (Nujol)/cm⁻¹ 3039, 1671, 1614, 993, 932, 810and 722; NMR δ_(H) (400 MHz, DMSO-d₆) 0.85 (6H, s), 1.16-1.19 (2H, m),1.3-1.4 (4H, m), 1.48-1.6 (4H, m), 1.75 (2H, m), 2.14 (1H, m), 3.92 (2H,m), 5.10-5.20 (2H, m), 5.75-5.85 (1H, m), 8.7 (2H, br s) and 9.0 (1H, brs); Anal. Calcd for C₁₆H₂₇N₂Cl.0.2 H₂O: C, 67.09; H, 9.64; N, 9.78.Found: C, 67.09; H, 9.56; N, 9.53.

Example 7 N-Allyl-1-adamantanecarboximidamide hydrochloride

This was prepared from 1-adamantanecarbonitrile by the method of example1 using allylamine (3 eq) instead of ammonia. The title compound wasisolated (298 mg, 90%) as a white crystalline solid: mp 252-254° C.; IRν_(max) (Nujol)/cm⁻¹ 3185, 3031, 1678, 1613, 1257, 799, 751 and 717; NMRδ_(H) (400 MHz, DMSO-d₆) 1.65-1.70 (6H, m), 1.9-2.0 (6H, m), 2.04 (3H,s), 3.95 (2H, m), 5.1-5.2 (2H, m), 5.75-5.85 (1H, m), 8.71 (1H, s), 8.79(1H, s) and 9.15 (1H, s); Anal. Calcd for C₁₄H₂₃N₂Cl: C, 65.99; H, 9.10;N, 10.99. Found: C, 65.92; H, 9.04; N, 11.05.

Example 8 N-Ethyl-1-adamantanecarboximidainide hydrochloride

This was prepared from 1-adamantanecarbonitrile by the method of example1 using 2-M ethylamine in MeOH (3 eq) in place of ammonia and the titlecompound isolated (175 mg, 55%) as a white crystalline solid: mp 315° C.(dec); IR ν_(max) (Nujol)/cm⁻¹ 3191, 3030, 1682, 1616, 1354, 810 and766; NMR δ_(H) (400 MHz, DMSO-d₆) 1.10 (3H, t, J 7.0 Hz), 1.6-1.7 (6H,m), 1.85-1.90 (6H, m), 2.0-2.05 (3H, m), 3.30 (2H, pent, J 7.0 Hz), 8.67(1H, s), 8.71 (1H, s) and 8.86 (1H, s); Anal. Calcd for C₁₃H₂₃N₂Cl: C,64.31; H, 9.55; N, 11.54. Found: C, 64.27; H, 9.56; N, 11.54.

Example 9 N-Benzyl-1-adamantanecarboximidamide hydrochloride

This was prepared from 1-adamantanecarbonitrile by the method of example1 using benzylamine (1.1 eq) in place of ammonia and the title compoundisolated (357 mg, 90%) as a white crystalline solid: mp 242-244° C.; IRν_(max) (Nujol)/cm⁻¹ 3049, 1677, 1605, 1240, 759, 728 and 703; NMR δ_(H)(400 MHz, DMSO-d₆) 1.65-1.70 (6H, m), 1.9-2.0 (6H, m), 2.05 (3H, s),4.58 (2H, s), 7.3-7.4 (5H, m), 8.80 (1H, s), 8.85 (1H, s) and 9.55 (1H,s); Anal. Calcd for C₁₈H₂₅N₂Cl: C,70.92; H, 8.27; N, 9.18. Found: C,70.62; H, 8.21; N, 9.18.

Example 10 N-(2-Dimethylaminoethyl)-1-adamantanecarboximidamidedihydrochloride

This was prepared from 1-adamantanecarbonitrile by the method of example1 using N,N-dimethylethylenediamine (3 eq) in place of ammonia and thetitle compound isolated (42 mg, 10%) as a white crystalline solid: mp293° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3192, 2581, 2469, 1697, 1605 and798; NMR δ_(H) (400 MHz, DMSO-d₆) 1.65-1.75 (6H, m), 1.94 (6H, s), 2.04(3H, s), 2.81 (6H, s), 3.27 (2H, m), 3.72 (2H, m), 8.98 (1H, s), 9.04(1H, s), 9.13 (1H, s) and 10 86 (1H, s); Anal. Calcd forC₁₅H₂₉N₃Cl₂.0.25 H₂O: C, 55.12; H, 9.10; N, 12.86. Found: C, 55.23; H,9.00; N, 12.89.

Example 11 3-(3,5-Dimethyl-1-adamantyl)propanimidamide hydrochloride

3-(3, 5-Dimethyl-1-adamantyl)propionitrile

A solution of 1-bromo-3,5-dimethyladamantane (1.0 g, 4.11 mmol),acrylonitrile (436 mg, 8.22 mmol) and1,1′-azobis(cyclohexanecarbonitrile) (50 mg, 0.21 mmol) in dry toluene(12 mL) was treated with tri-n-butyltin hydride (1.44 g, 4.93 mmol) atroom temperature, refluxed for 3.5 h, cooled, diluted with ether (30mL), washed with 0.2-M NH₄OH (30 mL), water (10 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography [SiO₂,CH₂Cl₂-hexane (0:100 to 100:0)] to give the product (771 mg, 86%) as acolourless oil: IR ν_(max) (liquid film)/cm⁻¹ 2899, 2841, 2247, 1545 and1359; NMR δ_(H) (400 MHz, CDCl₃) 0.81 (6H, s), 1.0-1.2 (6H, m),1.25-1.35 (6H, m), 1.53 (2H, t, J 4.2 Hz), 2.05-2.10 (1H, m) and 2.27(2H, tJ 4.2 Hz).

3-(3,5-Dimethyl-1-adamantyl)propanimidamide hydrochloride

This was prepared from 3-(3,5-dimethyl-1-adamantyl)propionitrile by themethod of example 1 and the title compound isolated (609 mg, 86%) as awhite crystalline solid: mp 246-248° C.; IR ν_(max) (Nujol)/cm⁻¹ 3076,1681, 789 and 749; NMR δ_(H) (400 MHz, DMSO-d₆) 0.80 (6H, s), 1.08 (6H,q, J 12.5 Hz), 1.28 (6H, d J 2.6 Hz), 1.39 (2H, m), 2.02 (1H, m), 2.31(2H, m), 8.65 (2H, br s) and 8.99 (2H, br s); Anal. Calcd forC₁₅H₂₅N₂Cl.0.2 NH₄Cl: C, 63.99; H, 9.95; N, 10.95. Found: C, 64.15; H,9.98; N, 10.87.

Example 12 3-Methyl-1-adamantanecarboximidamide hydrochloride

3-Methyl-1-adamantanecarbonitrile

This was prepared from 3-methyl-1-adamantanecarboxylic acid by themethod of example 1 and the product (1.81 g, 80%) isolated as a palebrown waxy solid: IR ν_(max) (Nujol)/cm⁻¹ 2923, 2853, 2233, 1456, 1377,1360, 1343, 1161 and 1111; NMR δ_(H) (400 MHz, CDCl₃) 0.85 (3H, s), 1.45(4H, m), 1.63 (2H, m), 1.74 (2H, s), 1.94 (4H, m) and 2.07 (2H, m).

3-Methyl-1-adamantanecarboximidamide hydrochloride

This was prepared from 3-methyl-1-adamantanecarbonitrile by the methodof example 1 and the title compound (1.26 g, 95%) isolated as a whitecrystalline solid: mp 255-257° C.; IR ν_(max) (Nujol)/cm⁻¹ 3222, 3084,2923, 2853, 1674, 1502, 1456, 1376, 1087 and 737; NMR δ_(H) (400 MHz,DMSO-d₆) 0.83 (3H, s), 1.42 (4H, m), 1.58 (4H, m), 1.77 (4H, m), 2.07(2H, m), 8.61 (2H, br s) and 8.99 (2H, br s); NMR δ_(C) (100 MHz,DMSO-d₆) 28.1, 30.2, 30.8, 34.9, 37.5, 42.7, 44.6 and 177.0.

Example 13 3,5,7-Trimethyl-1-adamantanecarboximidamide hydrochloride

3,5,7-Trimethyl-1-adamantanecarbonitrile

This was prepared from 3,5,7-trimethyl-1-adamantanecarboxylic acid bythe method of example 1 and the product (2.01 g, 88%) isolated as a waxysolid: IR ν_(max) (Nujol)/cm⁻¹ 2923, 2864, 2230, 1456, 1377, 1358, 1350,1257, 1095 and 912; NMR δ_(H) (400 MHz, CDCl₃) 0.90 (9H, s), 1.12 (6H,m) and 1.60 (6H, s).

3,5,7-Trimethyl-1-adamantanecarboximidamide hydrochloride

This was prepared from 3,5,7-trimethyl-1-adamantanecarbonitrile by themethod of example 1 and the title compound (0.98 g, 98%) isolated as awhite crystalline solid: mp 325° C.; IR ν_(max) (Nujol)/cm⁻¹ 3266, 3094,2923, 2854, 1666, 1517, 1454, 1376, 1365, 1113, 1098 and 741; NMR δ_(H)(400 MHz, DMSO-d₆) 0.86 (9H, s), 1.09 (6H, m), 1.44 (6H, s), 8.59 (2H,br s) and 8.99 (2H, br s); NMR δ_(C) (100 MHz, DMSO-d₆) 30.0, 31.8,40.9, 43.5, 49.2 and 176.7.

Example 14 3-(4-Nitrophenyl)-1-adamantanecarboximidamide hydrochloride

3-(4-Nitrophenyl)-1-adamantanecarbonitrile

This was prepared from 3-(4-nitrophenyl)-1-adamantanecarboxylic acid bythe method of example 1 and the product (0.92 g, 93%) isolated as a palebrown solid: IR ν_(max) (Nujol)/cm⁻¹ 2923, 2854, 2235, 1594, 1516, 1458,1377, 1353, 1111 and 858; NMR δ_(H) (400 MHz, CDCl₃) 1.79 (2H, m), 1.94(4H, m), 2.11 (4H, m), 2.21 (2H, s), 2.30 (2H, m), 7.49 (2H, m) and 8.20(2H, m).

3-(4-Nitrophenyl)-1-adamantanecarboximidamide hydrochloride

This was prepared from 3-(4-nitrophenyl)-1-adamantanecarbonitrile by themethod of example 1 and the title compound (0.22 g, 77%) isolated as awhite crystalline solid: mp 256-259° C.; IR ν_(max) (Nujol)/cm⁻¹ 3448,3365, 3314, 3160, 3074, 2923, 2854, 1686, 1664, 1608, 1596, 1512, 1455,1377, 1351, 741 and 697; NMR δ_(H) (400 MHz, DMSO-d₆) 1.72 (2H, m), 1.93(8H, m), 2.09 (2H, s), 2.25 (2H, m), 7.75 (2H, m), 8.21 (2H, m), 8.73(2H, br s) and 8.93 (2H, br s).

Example 15 2-(1-Adamantyl)butanimidamide hydrochloride

2-(1-Adamantyl)butanenitrile

A solution of diisopropylamine (0.45 mL, 3.2 mmol) in dry THF (15 mL) at−78° C. was treated with n-BuLi (1.6-M, 2 mL, 3.2 mmol), stirred at −78°C. for 15 min, treated with a solution of 2-(1-adamantyl)acetonitrile(0.5 g, 2.9 mmol) in dry THF (5 mL) and stirred at −78° C. for 1 h.Ethyl iodide (0.26 mL, 3.2 mmol) was added dropwise, the solutionstirred at −78° C. for 2 h, allowed to warm to room temperature, treatedwith NH₄Cl solution (20 mL), extracted with EtOAc (3×10 mL), theextracts washed with brine (10 mL), dried (MgSO₄) and concentrated invacuo to give the product (0.56 g, 97%) as a pale brown solid: mp 53-54°C; IR ν_(max) (Nujol)/cm⁻¹ 2914, 2231, 1455, 1378, 1366, 1346, 1317,1091 and 979;.NMR δ_(H) (400 MHz, CDCl₃) 1.11 (3H, t, J 7.4 Hz), 1.49(1H, m), 1.74-1.64 (13H, m) and 2.06 (4H, m); Anal. Calcd forC₁₄H₂₁N.0.1 H₂O: C, 81.97; H, 10.42; N, 6.83. Found: C, 81.92; H, 10.68;N, 6.74.

2-(1-Adamantyl)butanimidamide hydrochloride

A suspension of NH₄Cl (1.38 g, 26 mmol) in dry toluene (8 mL) at 0° C.was treated dropwise with 2-M trimethylaluminium in toluene (13 mL, 26mmol), allowed to warm to room temperature and stirred for 2 h. Thissolution was added to a solution of 2-(1-adamantyl)butanenitrile (0.44g, 2.2 mmol) in dry toluene (10 mL) and the resulting solution refluxedfor 4 days, cooled to room temperature and poured into a slurry of SiO₂(5 g) and CHCl₃ (10 mL). The slurry was filtered, the filtrate treatedwith Na₂SO₄, concentrated in vacuo and the residue loaded on to the topof a silica column and purified by chromatography [SiO₂; EtOAc-MeOH (9:1to 4:1)] to give the title compound (0.38 g, 68%) as a white solid: mp223° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3332, 3157, 3071, 2925, 2852,1666, 1510, 1462, 1377 and 724; NMR δ_(H) (400 MHz, DMSO-d₆) 0.81 (3H,t, J 7.2 Hz), 1.39 (2H, m), 1.56-1.69 (11H, br m), 1.96 (3H, m), 2.13(1H, m) and 9.08 (4H, br m); NMR δ_(C) (100 MHz, DMSO-d₆) 11.8, 17.0,27.8, 34.1, 36.2, 39.5, 56.0 and 171.0.

Example 16 2-(1-Adamantyl)-3-phenylpropanimidamide hydrochloride

This was prepared from 2-(1-adamantyl)-2-phenylpropanenitrile by themethod of example 15 and the title compound (0.11 g, 46%) isolated as awhite crystalline solid: mp 147-148° C.; IR ν_(max) (Nujol)/cm⁻¹ 3250br, 2923, 2852, 1679, 1495, 1456, 1377, 1346, 1313, 1084, 739 and 699;NMR δ_(H) (400 MHz, DMSO-d₆) 1.51 (3H, m), 1.66 (6H, m), 1.79 (3H, m),2.01 (3H, m), 2.60 (1H, m), 2.96 (2H, m), 7.24 (5H, m), 8.60 (1H, br s),8.78 (1H, br s), 8.92 (1H, br s) and 9.05 (1H, br s).

Example 17 3-(1-Adamantyl)-2-phenylpropanimidamide hydrochloride

3-(1-Adamantyl)-2-phenylpropenenitrile

A solution of diethyl 1-cyano-1-phenylmethylphosphonate (10.97 g, 43.3mmol) in dry THF (60 mL) at 0° C. was treated with NaH (60% dispersionin oil, 1.7 g, 43.3 mmol), stirred at 0° C. for 40 min, warmed to roomtemperature for 20 min, treated with a solution of1-adamantanecarboxaldehyde (3.56 g, 21.7 mmol) in dry THF (10 mL) andheated at 60° C. for 16 h. The reaction mixture was cooled, treated withwater (50 mL), extracted with EtOAc (3×20 mL), the extracts washed withbrine (40 mL), dried (MgSO₄) and concentrated in vacuo. The resultingbrown oil was purified by chromatography [SiO₂, heptane-EtOAc (9:1)] andrecrystallised (heptane) to give the product (1.62 g, 28%) as a whitesolid: mp 107-108° C; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2852, 2218, 1497,1448, 1377, 1343, 1101, 910, 762, 750 and 689; NMR δ_(H) (400 MHz,CDCl₃) 1.76 (6H, m), 1.99 (6H, m), 2.07 (3H, m), 6.50 (1H, s), 7.37 (3H,m) and 7.51 (2H, m); Anal. Calcd for C₁₉H₂₁N: C, 86.65; H, 8.04; N,5.32. Found: C, 86.58; H, 8.09; N, 5.33.

3-(1-Adamantyl)-2-phenylpropanenitrile

A solution of 3-(1-adamantyl)-2-phenylpropenenitrile (600 mg, 2.28 mmol)in EtOAc (30 mL) was treated with 10% Pd/C (70 mg), hydrogenated at 50psi for 16 h, filtered through SiO₂ and concentrated in vacuo. Theresidue was purified by chromatography [SiO₂, EtOAc-heptane (1:1)] andthe resulting solid recrystallised (heptane) to give the product (552mg, 91%) as a white crystalline solid: mp 83-84° C; IR ν_(max)(Nujol)/cm⁻¹ 2912, 2852, 2239, 1497, 1453, 1377, 1355, 1346, 1105, 749,713 and 696; NMR δ_(H) (400 MHz, CDCl₃) 1.50 (1H, dd, J 14.3, 3.2 Hz),1.63 (9H, m), 1.72 (3H, m), 1.94 (1H, dd, J 14.3,10.4 Hz), 2.01 (3H, m),3.79 (1H, dd, J 10.4, 3.2 Hz) and 7.35 (5H, m); Anal. Calcd for C₁₉H₂₃N:C, 85.99; H, 8.73; N, 5.28. Found: C, 85.96; H, 8.90; N, 5.27.

3-(1-Adamantyl)-2-phenylpropanimidamide hydrochloride

This was prepared from 3-(1-adamantyl)-2-phenylpropanenitrile by themethod of example 15 and the title compound (92 mg, 60%) isolated as apale brown solid: mp 253° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3243, 2918,2853, 1680, 1496, 1455, 1377, 1105, 1080, 754, 721 and 705; NMR δ_(H)(400 MHz, DMSO-d₆) 1.40 (3H, m), 1.55 (7H, m), 1.68 (3H, m), 1.92 (3H,m), 2.15 (1H, m), 4.05 (1H, m), 7.31 (1H, m), 7.40 (2H, m), 7.52 (2H, m)and 9.01 (4H, br s).

Example 18 3-(1-Adamantyl)-3-phenylpropanimidamide hydrochloride

This was prepared from 3-(1-adamantyl)-3-phenylpropanenitrile by themethod of example 15 and the title compound (130 mg, 50%) isolated as apale yellow solid: mp 249° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3400-2800br, 2957, 1684, 1455, 1407, 1377, 772 and 704; NMR δ_(H) (400 MHz,DMSO-d₆) 1.37 (3H, m), 1.51 (6H, m), 1.60 (3H, m), 1.92 (3H, m), 2.91(3H, m), 7.25 (5H, m), 8.50 (2H, br s) and 9.00 (2H, br s).

II NMDA Receptor Binding

The NMDA receptor contains several distinct binding domains that canregulate opening of the cationic channel. The phencyclidine (PCP) siteof the NMDA receptor can be radiolabeled with[³H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-iminehydrogen maleate, [³H-MK-801]. The following describes the procedure fordetermining the affinity of compounds for the PCP site in rat corticalor cerebellar membranes.

Frozen rat cortex or cerebellum, homogenized in 10 volumes of ice cold0.32 M. sucrose is centrifuged at 1,000 g for 12 min and the supernatantstored on ice whilst the pellet was resuspended, rehomogenized andrecentrifuged twice more. The three final supernatants were pooled andcentrifuged at 30,000 g for 40 min at 4° C. to yield P₂ pellets. Thesewere resuspended in ice-cold distilled water, and centrifuged at 30,000g for 50 min at 4° C. Following three further washes in distilled water,the P₂ pellets were stored at −20° C. for at least 18 h. On the day ofthe assay, membrane pellets were thawed at room temperature, resuspendedin ice-cold distilled water and centrifuged at 30,000 g for 20 min. Thepellets were resuspended in 50 mM tris-HCl (pH:7.4) and recentrifugedtwice more before being resuspended in tris-HCl for immediate use in theassay. Binding assays were performed at equilibrium in a total volume of200 μl, containing, [³H]-MK-801 (5 nM final conc.), 10 μM glutamate, 10μM glycine, 160 μl of membrane preparation and additional drugs whereappropriate. Non-specific binding was determined using MK-801 (10 μM).The assay was incubated for 120 min at room temperature. The incubationwas terminated by rapid filtration through Whatman GF/B filters(pre-soaked in 0.1% PEI solution). The assay tubes and filters werewashed five times with 1 ml of ice cold assay buffer. The filters wereplaced in poly-Q mini vials with approximately 5 ml of scintillationfluid. The vials are then shaken and left for at least 8 hours beforebeing counted on a liquid scintillation counter. To determine the freeligand concentration 3 aliquots (20 μl) of the [³H]-MK-801 workingsolution were also counted. Concentration response data for drugs wasanalysed using a 4 parameter equation fitted by non linear regression.This yielded the half maximally effective drug concentration (IC₅₀) andHill coefficient.

The data obtained from these assays are presented in Table 1. The dataclearly demonstrate that the compounds of the invention are active asNMDA antagonists and have favourable ratios of cortical to cerebellarbinding affinity indicating that the compounds will be well-tolerated invivo.

TABLE 1 Binding Affinities at Cortical and Cerebellar NMDA ReceptorsIC₅₀(μM) IC₅₀(μM) Compound Cortex Cerebellum Ratio Example 1 28 6 4.7Example 2 291 Example 3 188 105 1.8 Example 4 122 56 2.2 Example 5 82 561.5 Example 6 31 Example 7 698 297 2.4 Example 8 1000 Example 9 754 3881.9 Example 10 1000 Example 11 78 48 1.6 Example 12 96 36 2.7 Example 1343 18 2.4 Example 14 406 234 1.7 Example 15 144 46 3.1 Example 16 52 271.9 Example 17 16 Example 18 27

What is claimed is:
 1. A method of treating a condition treatable byantagonism of the N-methyl-D-aspartate receptor, which comprisesadministering to a patient in need of said treatment of said condition,a pharmaceutically effective dose of a compound of the formula (1):

wherein X is an alkylene chain containing 0, 1, 2, 3 or 4 carbon atoms;R¹, R² and R³ are independently selected from hydrogen, alkyl and aryl;R⁴, R⁵ and R⁶ are independently selected from hydrogen, alkyl, aryl,halogen and alkoxy; or a prodrug or pharmaceutically acceptable saltthereof.
 2. The method of claim 1 wherein X is an alkylene chaincontaining 1, 2, 3 or 4 carbon atoms and one or more carbon atom(s) ofthe chain X is/are independently substituted by substituent group(s)selected from alkyl and aryl.
 3. The method of claim 2 wherein asubstituted carbon atom is substituted by one substituent group selectedfrom alkyl and aryl.
 4. The method of claim 2 wherein a substitutedcarbon atom is substituted by two substituent groups independentlyselected from alkyl and aryl.
 5. The method of claim 2, wherein thesubstituent group(s) are selected from methyl, ethyl, phenyl and benzyl.6. The method of claim 2, wherein one carbon atom of the chain X issubstituted.
 7. The method of claim 1 wherein X is (CH₂)_(n) where n=0to
 4. 8. The method of claim 1 wherein X is an alkylene chain containing1 or 2 carbon atoms in the chain.
 9. The method of claim 7 wherein n=0.10. The method of claim 1 wherein R¹ and R² are hydrogen and R³ isselected from hydrogen, alkyl and aryl.
 11. The method of claim 1wherein R¹, R² and R³ are hydrogen.
 12. The method of claim 1 wherein atleast one of R⁴, R⁵ and R⁶ is alkyl, aryl, halogen or alkoxy.
 13. Themethod of claim 1 to wherein R⁴ is selected from hydrogen, alkyl andhalogen.
 14. The method of claim 1 wherein R⁵ is selected from hydrogenand alkyl.
 15. The method of claim 1 wherein R⁶ is selected fromhydrogen and alkyl.
 16. The method of claim 1 wherein X has 0 carbonatoms; R¹, R² and R³ are hydrogen; R⁴ and R⁵ are CH₃; and R⁶ ishydrogen.
 17. The method of claim 1 wherein X has 0 carbon atoms; R¹, R²and R³ are hydrogen; R⁴ is methyl; and R⁵=R⁶=hydrogen or methyl.
 18. Themethod of claim 2 wherein X has one carbon atom and is substituted by anethyl or benzyl group; and R¹, R², R³, R⁴, R⁵ and R⁶ are hydrogen. 19.The method of claim 1 wherein X has one carbon atom and isunsubstituted; R¹, R² and R³ are hydrogen; R⁴ and R⁵ are methyl and R⁶is hydrogen.
 20. The method of claim 1 wherein said condition treatableby blockade of the N-methyl-D-aspartate receptor is selected from thegroup consisting of ischaemic stroke, haemorrhagic stroke, Alzheimer'sdisease, multiple sclerosis, acute pain, chronic pain, epilepsy,drug-induced optic neuritis, peripheral neuropathy, myelopathy,ischaemic retinopathy, and glaucoma.